Local Delivery of the Toll-Like Receptor 9 Ligand CpG Downregulates Host Immune and Inflammatory Responses, Ameliorating Established Leishmania (Viannia) panamensis Chronic Infection

Ehrlich, Allison; Fernández, Olga Lucía; Rodríguez-Pinto, Daniel; Castilho, Tiago Moreno; Caridad, Maria J. Corral; Goldsmith-Pestana, Karen; Saravia, Nancy Gore; McMahon-Pratt, Diane

doi:10.1128/iai.00981-16

Cited by 11 publications

(10 citation statements)

References 92 publications

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“…It has been reported that the immune stimulation triggered by CpG DNA induces a strong Th1 response, which is necessary to decrease parasite burden and to resolve the infection in a murine model of leishmaniasis (Ehrlich et al ., 2017). Our data suggest that Tv DNA pretreatment induces a sustained inflammatory response in infected female mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

ReducedTrichomonas vaginalisviability in mice pretreated with parasite DNA

et al. 2019

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Trichomonas vaginalis is an extracellular parasite that colonizes the human urogenital tract leading to trichomoniasis, the most common sexually-transmitted non-viral disease worldwide. The immune response plays a critical role in the host defense against this parasite. Trichomonas' DNA contains unmethylated CpG motifs (CpGDNA) that in other microorganisms act as modulators of the immune response. However, the molecular mechanisms responsible for CpGDNA immune modulation are still unclear. As macrophages participate in the first line of defense against infection, we investigated the type of immune response of murine macrophages to T. vaginalis DNA (TvDNA). We observed high expression of the proinflammatory cytokines IL-6 and IL-12p40 in macrophages stimulated with TvDNA. In contrast, the anti-inflammatory response, assessed by IL-10 and IL-13 mRNA expression was delayed. This suggests that the immune response induced by TvDNA is modulated through cytokine production, mediated partly by NADPH-oxidase activity, as TvDNA induced reactive species of oxygen production and a rounded morphology in macrophages indicative of an M1 phenotype. Furthermore, infected mice pretreated with TvDNA displayed persistent vulvar inflammation and decreased parasite viability consistent with higher proinflammatory cytokine levels during infection compared to untreated mice. Overall, our findings suggest that TvDNA pretreatment modulates the immune response favouring parasite elimination.

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Section: Resultsmentioning

confidence: 99%

ReducedTrichomonas vaginalisviability in mice pretreated with parasite DNA

et al. 2019

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“…There is considerable interest in harnessing TLR agonists as immunoprotective agents. The TLR9 CpG ODN agonists were among the most promising candidates, as preclinical studies demonstrated that TLR9 stimulation improved the survival of multiple species against a wide variety of pathogens (18)(19)(20)(21)(22)(23)(24). Despite that protective efficacy, the necessity that CpG ODN be delivered by injection limited the use of that agent.…”

Section: Discussionmentioning

confidence: 99%

Critical Role of B Cells in Toll-Like Receptor 7-Mediated Protection against Listeria monocytogenes Infection

et al. 2019

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Toll-like receptors (TLR) trigger the immune system to mount a rapid innate response capable of protecting the host from a wide variety of bacterial and viral pathogens. There is interest in harnessing TLR agonists to reduce the susceptibility of at-risk populations to infection. However, the widespread prophylactic use of TLR agonists has been compromised by the need to administer them by parenteral injection. An exception is the TLR7/8 agonist R848, which can boost gastrointestinal and systemic immunity when administered orally. This work examines the effect of R848 on host susceptibility to Listeria monocytogenes in a murine challenge model and describes the underlying mechanisms. Results show that prophylactic administration of R848 significantly reduces susceptibility to infection of BALB/c mice, an effect that lasts 1 week. Oral R848 directly stimulated B cells to produce cytokines and Ig. In the absence of B cells, R848-mediated protection was lost. These findings support the use of oral R848 to reduce the susceptibility of at-risk individuals to infection and identify the critical role of B cells in TLR7-mediated resistance to bacterial infection.

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“…CpG-ODNs effectiveness in the control of allergic responses can be explained by the TLR9 induced T helper 1 (Th1) response that in turn can prevent or reprogram the typical allergic Th2 polarization of the immune system ( Chu et al, 1997 ; Krieg, 2002 ; Krieg, 2002 ; Kline et al, 2002 ). In this context TLR9 has been shown to induce regulatory T cells (Tregs) as well which could potentially contribute to beneficial immunosuppression in allergic asthmatic patients ( Ehrlich et al, 2017 ; Moseman et al, 2004 ; Kim et al, 2016 ;), but also provide immune escape opportunity for SARS-CoV-2. Recent data presented by Grifoni et al show a predominant representation of a classic Th1 response to SARS-CoV-2 with little to no Th2 cytokines ( Grifoni et al, 2020 ).…”

Section: Multidisciplinary Clues That Reason the Proposed Role For Tlmentioning

confidence: 99%

TLR9 and COVID-19: A Multidisciplinary Theory of a Multifaceted Therapeutic Target

Bezemer

Garssen

2021

Front. Pharmacol.

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By mapping the clinical pathophysiology of the novel coronavirus disease 2019 (COVID-19) against insights from virology, immunology, genomics, epidemiology and pharmacology, it is here proposed that the pathogen recognition receptor called toll like receptor 9 (TLR9) might have a pivotal role in the pathogenesis of COVID-19. Severe Acute Respiratory Syndrome Coronavirus 2, is causing the greatest global social and economic disruption since world war II. Lack of a vaccine, lack of successful treatment and limitations of the healthcare workforce and resources needed to safeguard patients with severe COVID-19 on the edge of life, demands radical preventive measures. It is urgently needed to identify biomarkers and drug candidates so that vulnerable individuals can be recognized early and severe multi-organ complications can be prevented or dampened. The TLR9 COVID-19 hypothesis describes a mechanism of action that could explain a wide spectrum of manifestations observed in patients with severe COVID-19. The introduced hypothesis proposes biomarkers for identification of vulnerable individuals and positions TLR9 as a promising multifaceted intervention target for prevention and/or treatment of COVID-19. TLR9 agonists might have value as prophylactic vaccine adjuvants and therapeutic immune stimulators at the early onset of disease. Additionally, in this current manuscript it is proposed for the first time that TLR9 could be considered as a target of “inhibition” aimed to dampen hyperinflammation and thrombotic complications in vulnerable patients that are at risk of developing late stages of COVID-19. The readily availability of TLR9 modulating drug candidates that have reached clinical testing for other disorders could favor a fast track development scenario, an important advantage under the current high unmet medical need circumstances regarding COVID-19.

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Local Delivery of the Toll-Like Receptor 9 Ligand CpG Downregulates Host Immune and Inflammatory Responses, Ameliorating Established Leishmania (Viannia) panamensis Chronic Infection

Cited by 11 publications

References 92 publications

ReducedTrichomonas vaginalisviability in mice pretreated with parasite DNA

ReducedTrichomonas vaginalisviability in mice pretreated with parasite DNA

Critical Role of B Cells in Toll-Like Receptor 7-Mediated Protection against Listeria monocytogenes Infection

TLR9 and COVID-19: A Multidisciplinary Theory of a Multifaceted Therapeutic Target

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